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Testing the Addition of the Drug Apalutamide to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer

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ClinicalTrials.gov Identifier: NCT04134260
Recruitment Status : Recruiting
First Posted : October 22, 2019
Last Update Posted : February 7, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Study Description
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Brief Summary:
This phase III trial studies whether adding apalutamide to the usual treatment improves outcome in patients with lymph node positive prostate cancer after surgery. Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgens, or male sex hormones, can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may help stop or reduce the growth of prostate cancer cell growth by blocking the attachment of androgen to its receptors on cancer cells, a mechanism similar to stopping the entrance of a key into its lock. Adding apalutamide to the usual hormone therapy and radiation therapy after surgery may stabilize prostate cancer and prevent it from spreading and extend time without disease spreading compared to the usual approach.

Condition or disease Intervention/treatment Phase
Prostate Adenocarcinoma Stage I Prostate Cancer AJCC v8 Stage II Prostate Cancer AJCC v8 Stage IIA Prostate Cancer AJCC v8 Stage IIB Prostate Cancer AJCC v8 Stage IIC Prostate Cancer AJCC v8 Stage III Prostate Cancer AJCC v8 Stage IIIA Prostate Cancer AJCC v8 Stage IIIB Prostate Cancer AJCC v8 Stage IIIC Prostate Cancer AJCC v8 Stage IVA Prostate Cancer AJCC v8 Drug: Apalutamide Drug: Hormone Therapy Other: Quality-of-Life Assessment Other: Questionnaire Administration Radiation: Radiation Therapy Phase 3

Detailed Description:

PRIMARY OBJECTIVE:

I. Compare metastasis-free survival (MFS) of salvage radiation therapy (RT) and gonadotropin releasing hormone (GnRH) agonist/antagonist versus (vs.) RT/GnRH agonist/antagonist with apalutamide for patients with pathologic node-positive prostate cancer after radical prostatectomy with detectable prostate-specific antigen (PSA).

SECONDARY OBJECTIVES:

I. Compare health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]-26, EuroQol [EQ]-5 Dimension [D]-5 Level [L]), Brief Pain Inventory, Patient Reported Outcome Measurement Information System [PROMIS]-Fatigue) among the treatment arms.

II. Compare overall survival, biochemical progression-free survival, time to local-regional progression, time to castrate resistance, and cancer-specific survival among the treatment arms.

III. Compare the short-term and long-term treatment-related adverse events among the treatment arms.

EXPLORATORY OBJECTIVES:

I. Validate Decipher score for an exclusively node-positive population and use additional genomic information from Affymetrix Human Exon 1.0st array to develop and validate novel prognostic and predictive biomarkers.

II. Validate the PAM50-based classification of prostate cancer into luminal A, luminal B, and basal subtypes as prognostic markers and determine whether the luminal B subtype is a predictive marker for having a larger improvement in outcome from the addition of apalutamide.

III. To optimize quality assurance methodologies and processes for radiotherapy and imaging with machine learning strategies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care hormone therapy per physician discretion for 24 months. Patients also undergo standard of care pelvis and prostate bed radiation therapy 5 days per week over 5-6 or 7-8 weeks beginning within 90 days of randomization in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo standard of care hormone therapy and radiation therapy as in Arm I. Patients also receive apalutamide orally (PO) once daily (QD) on days 1-90. Cycles repeat every 90 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years, then annually thereafter.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 586 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase III Trial Incorporating Apalutamide and Advanced Imaging Into Salvage Treatment for Patients With Node-Positive Prostate Cancer After Radical Prostatectomy (INNOVATE*) *INtensifying Treatment for NOde Positive Prostate Cancer by VArying the Hormonal ThErapy
Actual Study Start Date : March 5, 2020
Estimated Primary Completion Date : November 1, 2026
Estimated Study Completion Date : November 1, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Apalutamide

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Arm I (hormone therapy, radiation therapy)
Patients receive standard of care hormone therapy per physician discretion for 24 months. Patients also undergo standard of care pelvis and prostate bed radiation therapy 5 days per week over 5-6 or 7-8 weeks beginning within 90 days of randomization in the absence of disease progression or unacceptable toxicity.
 Drug: Hormone Therapy
Receive hormone therapy
Other Names:
  • Chemotherapy-Hormones/Steroids
  • Endocrine Therapy
  • Hormonal Therapy
  • hormone treatment
  • Hormones

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo pelvis and prostate bed radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
Experimental: Arm II (hormone therapy, radiation therapy, apalutamide)
Patients undergo standard of care hormone therapy and radiation therapy as in Arm I. Patients also receive apalutamide PO QD on days 1-90. Cycles repeat every 90 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
 Drug: Apalutamide
Given PO
Other Names:
  • ARN 509
  • ARN-509
  • ARN509
  • Erleada
  • JNJ 56021927
  • JNJ-56021927

Drug: Hormone Therapy
Receive hormone therapy
Other Names:
  • Chemotherapy-Hormones/Steroids
  • Endocrine Therapy
  • Hormonal Therapy
  • hormone treatment
  • Hormones

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo pelvis and prostate bed radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation


Outcome Measures
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Primary Outcome Measures :
  1. Metastasis-free survival (MFS) [ Time Frame: From randomization to detection of metastatic disease or death from any cause, assessed up to 7.5 years ]
    Kaplan-Meier curves will be generated and metastasis-free survival compared between the two treatment groups by a logrank test, stratified by prostate specific antigen (PSA) level after prostatectomy (never detectable or rising). Cox regression modeling to assess and adjust for the effects of PSA stratum and other baseline covariates will also be performed. The proportional hazards assumption will be tested using Schoenfeld residuals and graphical methods. Martingale residual plots will be examined to determine the best functional form for incorporating covariates into the model. A competing risks analysis will also be performed with time to distant metastasis or death from prostate cancer as the event of interest and death from other causes as the competing risk. Cumulative incidence curves will be generated along with Fine-Gray's test. Patients alive and metastasis free will be censored as of the time of the last negative examination.


Secondary Outcome Measures :
  1. Quality of life (QOL) between the two treatment arms [ Time Frame: Up to 3 years post treatment ]
    Quality of life scores will be derived by constructing summary measures across domains from the various quality of life instruments (Expanded Prostate Cancer Index Composite-26, EuroQol (EQ)-5 Dimension (D)-5 Level (L), Brief Pain Inventory, and Patient Reported Outcome Measurement Information System-Fatigue). Calculated health utilities will be derived from the EQ-5D-5L instrument and used to produce a quality-adjusted life year survival estimate post-treatment. The area under the curve provides an estimate of the quality-adjusted, restricted mean survival time and will be compared between the two treatment arms as described in Glasziou et al (1990). QOL scores will be analyzed using mixed effects regression for longitudinal data to compare the profiles over time between the two treatment groups (Gibbons and Hedeker, 2000). The models will include treatment, time, and treatment-by-time interaction terms as fixed effects and subjects as a random effect.

  2. Overall survival (OS) [ Time Frame: From randomization until date of death or censored at last date known alive, assessed up to 7.5 years ]
    Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.

  3. Biochemical progression-free survival (bPFS) [ Time Frame: From randomization until biochemical recurrence or death from prostate cancer, assessed up to 7.5 years ]
    Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. In addition, competing risks analyses will be performed and cumulative incidence curves generated for bPFS with death from other (i.e., non-prostate cancer) causes treated as a competing event. Patients who die from non-prostate cancer related causes will be censored as of the date of death.

  4. Time to local-regional progression [ Time Frame: Up to 7.5 years ]
    Competing risks analyses will be performed and cumulative incidence curves generated for local-regional progression with death from other (i.e., non-prostate cancer) causes treated as a competing event.

  5. Time to castrate resistance [ Time Frame: Up to 7.5 years ]
    Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. Patients who die prior to resistance will be censored.

  6. Cancer-specific survival [ Time Frame: Up to 7.5 years ]
    Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. In addition, competing risks analyses will be performed and cumulative incidence curves generated for cancer-specific survival with death from other (i.e., non-prostate cancer) causes treated as a competing event. Patients who die from non-prostate cancer related causes will be censored as of the date of death.

  7. Incidence of adverse events [ Time Frame: Up to 7.5 years ]
    Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be tabulated by type, level of severity, and attribution for each treatment arm and the rate of events compared between treatment groups using chi-square or Fisher's exact tests.


Other Outcome Measures:
  1. MFS by Decipher genomic score [ Time Frame: Up to 7.5 years ]
    Will determine the ability of the Decipher test to predict for metastasis in a purely node-positive population. Subgroup analyses of MFS by Decipher genomic score (high risk or low/intermediate risk) will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.

  2. OS by Decipher genomic score [ Time Frame: Up to 7.5 years ]
    Will determine the ability of the Decipher test to predict for metastasis in a purely node-positive population. Subgroup analyses of OS by Decipher genomic score (high risk or low/intermediate risk) will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.

  3. PAM50-based classification of prostate cancer [ Time Frame: Up to 7.5 years ]
    Will validate the PAM50-based classification of prostate cancer into luminal A, luminal B, and basal subtypes as prognostic markers. Classifications of prostate cancer into Luminal A, Luminal B, and basal subtypes using the PAM50 method of classification. Subgroup analyses will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically (histologically) proven diagnosis of prostate adenocarcinoma. Any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
  • Any T-stage is eligible (American Joint Committee on Cancer [AJCC] 8th edition [ed])
  • Appropriate stage for study entry based on fluciclovine F-18 positron emission tomography (PET) scan (FACBC, Axumin) within 90 days prior to registration that is negative for distant metastatic (M1a, M1b, M1c) disease; Note that though every effort should be made to obtain a fluciclovine F-18 PET (FACBC, Axumin) scan; however, if the patient has already had a recent F-18 PSMA PET (PyLarify) scan or gallium Ga 68-labeled PSMA-11 (Ga-68 PSMA) PET scan or C-11 or F-18 choline PET scan within 90 days prior to registration (to include scan report) then repeat molecular imaging with a fluciclovine F-18 PET (FACBC, Axumin) scan will not be required.
  • Pathologically node positive disease with nodal involvement only in the pelvis in the prostatectomy specimen (including external iliacs, internal iliacs, and/or obturator nodes); peri-prostatic and peri-rectal nodes can also be considered regional lymphadenopathy and are allowed
  • History/physical examination within 90 days prior to registration
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 90 days prior to registration
  • Detectable PSA after radical prostatectomy. Detectable PSA is defined as serum PSA > 0 ng/mL at least 30 days after prostatectomy and within 180 days of registration and before start of GnRH agonist/antagonist
  • Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =< 180 days prior to registration are eligible (Note: patients who started on an oral antiandrogen are eligible if started =< 180 days and stopped prior to registration)
  • Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors (within 90 days prior to registration)
  • Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 90 days prior to registration)
  • Serum potassium >= 3.5 mmol/L within 90 days prior to registration
  • Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault (please use actual weight for calculation unless greater than 30% above ideal body weight then use the adjusted body weight) (within 90 days prior to registration)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject is eligible) (within 90 days prior to registration)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (within 90 days prior to registration)
  • Serum albumin >= 3.0 g/dL (within 90 days prior to registration)
  • Discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to registration
  • The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note: HIV testing is not required for eligibility for this protocol
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within 30 days prior to registration, if indicated. Note: HBV viral testing is not required for eligibility for this protocol
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 30 days prior to registration
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ) who has no evidence of disease for < 3 years must contact the principal investigator, Ronald Chen, Doctor of Medicine (MD)
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

  • Definitive radiologic evidence of metastatic disease (M1a, M1b or M1c) on molecular imaging (e.g. fluciclovine F-18 PET, F-18 PSMA, PSMA, F-18 choline 11)
  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration)
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Androgen deprivation therapy (ADT) prior to radical prostatectomy
  • Prior treatment with androgen receptor signaling inhibitor (including but not exclusive to a growing list of: abiraterone acetate, enzalutamide, apalutamide, darolutamide), unless started =< 180 days and stopped prior to registration, which is allowed
  • Current use of 5-alpha reductase inhibitor. NOTE: if the alpha reductase inhibitor is stopped prior to randomization the patient is eligible

  • History of any of the following:

    • Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year prior to registration, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal disease which may require treatment with surgery or radiation therapy)
    • Severe or unstable angina, myocardial infarction, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 12 months prior to registration
    • New York Heart Association functional classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification.)
    • History of any condition that in the opinion of the investigator, would preclude participation in this study

  • Current evidence of any of the following:

    • Known gastrointestinal disorder affecting absorption of oral medications
    • Active uncontrolled infection
    • Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment
    • Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily
    • Baseline moderate and severe hepatic impairment (Child-Pugh Class B & C)
    • Inability to swallow oral pills
    • Any current condition that in the opinion of the investigator, would preclude participation in this study
  • Patients must not plan to participate in any other therapeutic clinical trials while receiving treatment on this study
  • Patients with inflammatory bowel disease
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04134260


Locations
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Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ronald C Chen NRG Oncology
More Information
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Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT04134260    
Other Study ID Numbers: NRG-GU008
NCI-2019-06838 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GU008 ( Other Identifier: NRG Oncology )
NRG-GU008 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: October 22, 2019    Key Record Dates
Last Update Posted: February 7, 2024
Last Verified: February 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Genital Diseases
 Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs